DESCRIPTION (Investigator's Abstract): The main purpose of the proposed studies is to determine whether a major mechanism of action of Chronic Energy Intake Restriction (CEIR) to both prolong life and health by inhibiting development of diseases of aging is to down-regulate (control) rapid cell replication. To this end, the investigators propose to compare the influence of CEIR on replication of cells in each of the major rapidly replicating cell systems in mice of each of several autoimmune-prone strains. It is further proposed to study in some detail the influence of CEIR on the extraordinary compensatory burst of cell replication that follows partial hepatectomy and to determine whether CEIR influences the initiation, ongoing replication and cessation of this replicative burst. Finally, it will be determined whether CEIR inhibits either or both the benign proliferation which occurs in the Harderian gland or the malignancies of breast, lymphoid tissue or salivary gland which develop in mice transgenic for the Ha-ras oncogene that is driven by murine mammary tumor virus (MMTV) LTR, or the lymphomas and breast tumors which occur in mice transgenic for the c-myc gene driven by MMTV LTR, or the lymphomas, which occur in the mice transgenic for the c-myc gene driven by immunoglobulin gene LTR, or the lymphomas, breast tumor and salivary gland tumors which occur in the F1 hybrids between mice transgenic for the above Ha-ras MMTV LTR and mice transgenic for c-myc MMTV LTR. Also proposed to be determined is whether or not prolactin levels which the investigators can lower greatly by CEIR, and can raise or lower at will by pituitary transplantation or treatment by daily I.P. injections of CV-205-502, represent a crucial influence on each of these forms of cell proliferation. The applicants will also seek to define the controls of the proliferative processes that are influenced by CEIR through analyses of gene expression at the mRNA level for what are deemed to be the most likely crucial proto-oncogenes, transoncogenes and/or growth factor genes involved in control of these different proliferative processes. These investigations should contribute significantly to understanding how proliferative processes of cells and proliferative processes in cellular regeneration that may be involved in numerous diseases of aging can be influenced and controlled by dietary intervention. Another aim of the proposal is to learn how CEIR controls premalignant and malignant proliferations that are associated with expression of certain proto-oncogenes. These investigations could become central issues in efforts to extend life and health in humans by dietary intervention.